Functional diversity among resident macrophages (RM), immigrant macrophages (IM), and blood monocytes is widely believed to reflect differences in levels of maturation, stimulation and activation of a single cell type. Available evidence, however, is wholly compatible with the alternative explanation that divergent pathways of development generate functionally characteristic subclasses represented by monocytes and IM on the one hand and RM on the other. To test current hypotheses we propose to study: 1) The cytokinetics of renewal of RM populations in the lung and peritoneal cavity in mice deprived of blood monocytes by 89Sr irradiation of bone marrow, 2) The entry of isotopically labeled or phenotypically marked blood cells into RM pools in the histocompatible parabiotic linkage C57B1/6N:C59B1/6bgbg (beige) and 3) The degree of functional modulation of RM inducible in vivo by antigen reactive syngeneic lymphocytes in 89Sr monocyte depleted mice. In addition to resolving questions concerning the origins and renewal of macrophages populations, results of the investigation should provide substantial information concerning the basis for functional heterogeneity among these cells and its signficance in host defense mechanisms.